Seipin regulates ER–lipid droplet contacts and cargo delivery

Abstract Seipin is an endoplasmic reticulum ( ER ) membrane protein implicated in lipid droplet ( LD ) biogenesis and mutated in severe congenital lipodystrophy ( BSCL 2). Here, we show that seipin is stably associated with nascent ER – LD contacts in human cells, typically via one mobile focal point per LD . Seipin appears critical for such contacts since ER – LD contacts were completely missing or morphologically aberrant in seipin knockout and BSCL 2 patient cells. In parallel, LD mobility was increased and protein delivery from the ER to LD s to promote LD growth was decreased. Moreover, while growing LD s normally acquire lipid and protein constituents from the ER , this process was compromised in seipin‐deficient cells. In the absence of seipin, the initial synthesis of neutral lipids from exogenous fatty acid was normal, but fatty acid incorporation into neutral lipids in cells with pre‐existing LD s was impaired. Together, our data suggest that seipin helps to connect newly formed LD s to the ER and that by stabilizing ER – LD contacts seipin facilitates the incorporation of protein and lipid cargo into growing LD s in human cells.